Indoleamine 2,3-dioxygenase (IDO; MW 48,000; EC 1.13.11.42) is a heme-containing enzyme that is the first and rate-limiting enzyme in mammalian tryptophan metabolism. IDO catalyzes the oxidation of the essential amino acid tryptophan to N-formylkynurenine by dioxygen and is responsible for processing tryptophan in the human body. IDO is known to be inhibited in a non-specific manner by general inhibitors of heme-containing enzymes. Also, certain tryptophan (substrate) analogues such as 1-methyl-L-tryptophan (1MT) and beta-(3-benzofuranyl)-DL-alanine are competitive inhibitors of IDO (Sono, M. and Cady, S. G. (1989) Biochemistry 28:5392; and Cady, S. G. & Sono, M. (1991) Arch. Biochem. Biophys. 291:326-333).
Interferon gamma is one of several potent inducers of IDO expression. During persistent immune activation stimulated by high levels of interferon gamma, the availability of free serum tryptophan is diminished by IDO. As a consequence, serotonin production is also reduced. These changes combined with the accumulation of neuroactive kynurenine metabolites such as quinolinic acid (also induced by IDO) contribute to the development of neurologic/psychiatric disorders and is a factor in several mood disorders as well as related symptoms in chronic diseases characterised by IDO activation and tryptophan degradation, such as acquired immune deficiency syndrome (AIDS), Alzheimer's Disease, several types of depression, and cancer. (Wirleitner, Curr. Med. Chem. 10, 1581-91 (2003)).
IDO activity is also involved in the development of age-related nuclear cataracts. IDO is the first and rate-limiting enzyme in UV filter biosynthesis in the ocular lens. UV filter compounds derived from tryptophan degradation (kynurenine and 3-hydroxylkynurenine glucoside) modify proteins present in the human lens. These UV filter adducts increase in amount with age and have been reported (Takikawa et al., Adv. Exp. Med. Biol. 467, 241 (1999)) as responsible for the gradual opacification of the lens known as age-related nuclear cataract. An IDO inhibitor will block this natural process (Takikawa et al., Exp. Eye Res. 72, 271 (2001))
IDO expression is also involved in suppression of the immune response by blocking local T-lymphocyte proliferation. T-lymphocytes are extremely sensitive to tryptophan shortage and arrest in the G1 phase of the cell cycle under conditions of tryptophan depletion. Such suppression of T-cell mediated immune response is a factor in many diseases, including autoimmune diseases, allogenic rejection, neurodegenerative disorders, depression, bacterial infections, viral infections (such as the Human Immunodeficiency Virus (HIV)) and cancer (Swanson et al., Am. J. Respir. Cell Mol. Biol. 30, 311 (2003); Sarkhosh et al., J. Cell. Biochem. 90, 206 (2003); Mellor et al., J. Immunol. 171, (2003); and Wirleitner et al. Current Medicinal Chemistry, 10, 1581-1591 (2003)). IDO inhibitors are useful for regulation of T-cell mediated immune responses (U.S. Pat. No. 6,482,416, U.S. Pat. No. 6,451,840 and Munn et al. U.S. 2004/0234623) Also, IDO activity in the placenta is important in preventing allogenic rejection of a fetus as exemplified by fetus rejection upon administration of the IDO inhibitor 1-methyl-L-tryptophan (1MT).
Most human tumors have been found to express IDO constituitively. Mouse tumor cells from preimmunized mice have been shown to protect themselves against rejection by expressing IDO; an effect that is abrogated by administration of 1MT. Efficacy of cancer therapies would then be improved by concomitant administration of an IDO inhibitor. (Uyttenhove et al., Nat. Med. 9, 1269-1274 (2003); Prendergast et al. WO 2004/094409 and WO 2004/093871; and Munn et al. U.S. 2004/0234623).
IDO inhibitors would be useful for suppression of mood disorders and for treatment of other diseases characterised by pathology of the IDO mediated tryptophan metabolic pathway, including viral infections such as in AIDS, bacterial infections such as in Lyme disease and Streptococcal infections, neurodegenerative disorders (e.g. Alzheimer's, Huntington's and Parkinson's Diseases), depression, cancer (including T-cell leukemia and colon carcinoma), conditions of the eye (e.g. cataracts and age-related yellow) and autoimmune disorders.